Cryptococcus neoformans is an encapsulated pathogenic yeast that causes pulmonary infections and meningoencephalitis in humans and other animals. During the last 20 years, there has been a dramatic increase in the incidence of cryptococcosis throughout the world that mirrors the increase in not only HIV infections, but also in the growing number of immuno compromised patients. Loss of CD4+ T cells predisposes patients to progressive infection with C. neoformans--this emphasizes the role of cell mediated immunity in host resistance. Our long-term corporate goals are to discover new drugs for the treatment of fungal diseases and to develop vaccines against a number of human pathogenic fungi. In this Phase I STTR proposal, we plan to develop a safe and effective vaccine against C. neoformans. We will use a novel antigen delivery system and test a number of C. neoformans proteins as vaccine candidates. We will accomplish this in two specific aims: Specific Aim One: Engineer yeast cells to express each of five C. neoformans proteins using recombinant DNA technology. Specific Aim Two: Test the in vivo efficacy of each vaccine formulation to protect vaccinated animals against a challenge of C. neoformans. This work will be a prelude to work in Phase II that will include detailed testing for in vivo efficacy and safety of each vaccine candidate. Ultimately, the Phase I, Phase II and Phase lll research will lead to the development of a vaccine against C. neoformans